Salt and Crystalline Forms Thereof of a Drug

ABSTRACT

A crystalline form of a drug, ways to make it, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.

This application is a continuation of and claims the benefit of priorityof U.S. patent application Ser. No. 13/595,585, filed Aug. 27, 2012, nowU.S. Pat. No. 8,648,093 (“the '093 patent”), which is a continuation ofand claims the benefit of priority of U.S. patent application Ser. No.12/763,476, filed Apr. 20, 2010, now U.S. Pat. No. 8,273,892 (“the '892patent”), which in turn is a continuation of and claims the benefit ofpriority of U.S. patent application Ser. No. 11/245,561, filed Oct. 7,2005, now U.S. Pat. No. 7,728,143 (“the '143 patent”); the '093 patentis also a continuation of and claims the benefit of priority of U.S.patent application Ser. No. 12/701,254, filed Feb. 5, 2010, now U.S.Pat. No. 8,252,813 (“the '813 patent”), which in turn is a continuationof and claims the benefit of priority of the '143 patent; all of theforegoing of which claim priority to U.S. Provisional Patent ApplicationSer. No. 60/617,334, filed Oct. 8, 2004; the entire disclosures of allof the foregoing of which are incorporated by reference herein.

FIELD OF THE INVENTION

This invention pertains to a salt and crystalline forms thereof of adrug, ways to make it, compositions containing it and methods oftreatment using it.

BACKGROUND OF THE INVENTION

Crystallinity of drugs effects, among other physical and mechanicalproperties, their solubility, dissolution rate, hardness,compressability and melting point. Because these properties may, inturn, effect a drug's manufacture and their utility, there is anexisting need in the chemical and therapeutic arts for identification ofcrystalline forms of drugs and ways of reproducibly making them.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a powder X-ray diffraction pattern of crystallineD-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt).

FIG. 2 shows a powder X-ray diffraction pattern of crystallineD-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt).

SUMMARY OF THE INVENTION

One embodiment of this invention pertains to D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt).

Another embodiment pertains to D-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt).

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) characterized, when measured at about 25° C. with Cu—Kαradiation, by the powder diffraction pattern shown in FIG. 1.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) characterized, in the monoclinic crystal system and P 21/C or P21/M space group, when measured with Mo—Kα radiation at about 25° C., byrespective lattice parameters a, b and c of about 16.4460 Å, 21.4010 Åand 5.3050 Å and α of about 109°.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) having substantial crystalline purity and characterized, whenmeasured at about 25° C. with Cu—Kα radiation, by the powder diffractionpattern shown in FIG. 1.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) having substantial crystalline purity and characterized, in themonoclinic crystal system and P 21/C or P 21/M space group, whenmeasured with Mo—Kα radiation at about 25° C., by respective latticeparameters a, b and c of about 16.4460 Å, 21.401 Å and 5.3050. Å and βof about 109°.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) having substantial crystalline purity and substantial chemicalpurity and characterized, when measured at about 25° C. with Cu—Kαradiation, by the powder diffraction pattern shown in FIG. 1.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) having substantial crystalline purity and substantial chemicalpurity and characterized, in the monoclinic crystal system and P 21/C orP 21/M space group, when measured with Mo—Kα radiation at about 25° C.,by respective lattice parameters a, b and c of about 16.4460 Å, 21.4010Å and 5.3050 Å and 0 of about 109°.

Still another embodiment pertains to a composition comprising anexcipient and a therapeutically acceptable amount of crystallineD-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) characterized, when measured at about 25° C. with Cu—Kαradiation, by the powder diffraction pattern shown in FIG. 1.

Still another embodiment pertains to a composition comprising anexcipient and a therapeutically acceptable amount of crystallineD-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) characterized, in the monoclinic crystal system and P 21/C or P21/M space group, when measured with Mo—Kα radiation at about 25° C., byrespective lattice parameters a, b and c of about 16.4460 Å, 21.4010 Åand 5.3050 Å and 0 of about 109°.

Still another embodiment pertains to a method for treating bacterialinfections in a fish or a mammal comprising administering thereto atherapeutically effective amount of crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) characterized, when measured at about 25° C. with Cu—Kαradiation, by a powder diffraction pattern shown in FIG. 1.

Still another embodiment pertains to a method for treating bacterialinfections in a fish or a mammal comprising administering thereto atherapeutically effective amount of crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) characterized, in the monoclinic crystal system and P 21/C or P21/M space group, when measured with Mo—Kα radiation at about 25° C., byrespective lattice parameters a, b and c of about 16.4460 Å, 21.4010 Åand 5.3050 Å and 0 of about 109°.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) characterized, when measured at about 25° C. withCu—Kα radiation, by the powder diffraction pattern shown in FIG. 2.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) characterized, in the monoclinic crystal system and P21/C or P 21/M space group, when measured with Mo—Kα radiation at about25° C., by respective lattice parameters a, b and c of about 8.2490 Å,29.9840 Å and 12.5070 Å and 0 of about 105°.

Still another embodiment pertains to a crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) having substantial crystalline purity andcharacterized, when measured at about 25° C. with Cu—Kα radiation, bythe powder diffraction pattern shown in FIG. 2.

Still another embodiment pertains to a crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) having substantial crystalline purity andcharacterized, in the monoclinic crystal system and P 21/C or P 21/Mspace group, when measured with Mo—Kα radiation at about 25° C., byrespective lattice parameters a, b and c of about 8.2490 Å, 29.9840 Åand 12.5070 Å and 0 of about 105°.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) having substantial crystalline purity and substantialchemical purity and characterized, when measured at about 25° C. withCu—Kα radiation, by the powder diffraction pattern shown in FIG. 2.

Still another embodiment pertains to crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) having substantial crystalline purity and substantialchemical purity and characterized, in the monoclinic crystal system andP 21/C or P 21/M space group, when measured with Mo—Kα radiation atabout 25° C., by respective lattice parameters a, b and c of about8.2490 Å, 29.9840 Å and 12.5070 Å and 0 of about 105°.

Still another embodiment pertains to a composition comprising anexcipient and a therapeutically acceptable amount of crystallineD-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) characterized, when measured at about 25° C. withCu—Kα radiation, by the powder diffraction pattern shown in FIG. 2.

Still another embodiment pertains to a composition comprising anexcipient and a therapeutically acceptable amount of crystallineD-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) characterized, in the monoclinic crystal system and P21/C or P 21/M space group, when measured with Mo—Kα radiation at about25° C., by respective lattice parameters a, b and c of about 8.2490 Å,29.9840 Å and 12.5070 Å and 0 of about 105°.

Still another embodiment pertains to a method for treating bacterialinfections in a fish or a mammal comprising administering thereto atherapeutically effective amount of crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) characterized, when measured at about 25° C. withCu—Kα radiation, by a powder diffraction pattern shown in FIG. 2.

Still another embodiment pertains to a method for treating bacterialinfections in a fish or a mammal comprising administering thereto atherapeutically effective amount of crystalline D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) characterized, in the monoclinic crystal system and P21/C or P 21/M space group, when measured with Mo—Kα radiation at about25° C., by respective lattice parameters a, b and c of about 8.2490 Å,29.9840 Å and 12.5070 Å and 0 of about 105°.

Still another embodiment pertains to a process for making D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) comprising dehydrating D-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt).

Still another embodiment pertains to D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate (salt) prepared as described in thepreceding embodiment.

Still another embodiment pertains to a process for making D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) by crystallization of D-glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoro2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazendin-1-yl)-4-oxo-3-quinolinecarboxylate(salt) from water, with or without alcohol.

Still another embodiment pertains to D-glucitol,1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoropyridin-2-yr)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) prepared as described in the preceding embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The term “alcolol,” as used herein, means a compound having formulaR¹OH, wherein R¹ is C₁-alkyl, C₂-alkyl, C₃-alkyl, C₄-alkyl, C₅-alkyl orC₆-alkyl.

The term “C₁-alkyl,” as used herein, means methyl.

The term “C₂-alkyl,” as used herein, means ethyl.

The term “C₃-alkyl,” as used herein, means prop-1-yl and prop-2-yl(isopropyl).

The term “C₄-alkyl,” as used herein, means but-1-yl, but-2-yl,2-methylprop-1-yl and 2-methylprop-2-yl (tert-butyl).

The term “C₅-alkyl,” as used herein, means 2,2-dimethylprop-1-yl(neo-pentyl), 2-methylbut-1-yl, 2-methylbut-2-yl, 3-methylbut-1-yl,3-methylbut-2-yl, pent-1-yl, pent-2-yl and pent-3-yl.

The term “C₆-alkyl,” as used herein, means 2,2-dimethylbut-1-yl,2,3-dimethylbut-1-yl, 2,3-dimethylbut-2-yl, 3,3-dimethylbut-1-yl,3,3-dimethylbut-2-yl, 2-ethylbut-1-yl, hex-1-yl, hex-2-yl, hex-3-yl,2-methylpent-1-yl, 2-methylpent-2-yl, 2-methylpent-3-yl,3-methylpent-1-yl, 3-methylpent-2-yl, 3-methylpent-3-yl,4-methylpent-1-yl and 4-methylpent-2-yl.

The term “crystalline,” as used herein, means having a regularlyrepeating arrangement of molecules or external face planes.

The term “substantial crystalline purity,” as used herein, means atleast about 95% crystalline purity, preferably about 97% crystallinepurity, more preferably about 99% crystalline purity, and mostpreferably about 100% crystalline purity.

The term “crystalline purity,” as used herein, means percentage of acrystalline compound in a sample which may contain an amorphous form ofthe same compound, at least one other crystalline form of the compoundor a mixture thereof.

The term “substantial chemical purity,” as used herein, means about 95%chemical purity, preferably about 97% chemical purity, more preferablyabout 98% chemical purity, and most preferably about 100% chemicalpurity.

The term “chemical purity,” as used herein, means percentage of aparticular compound in a sample.

Unless stated otherwise, percentages stated throughout thisspecification are weight/weight (w/w) percentages.

The term “amorphous,” as used herein, means essentially withoutregularly repeating arrangement of molecules or external face planes.

The term “mixture,” as used herein, means a combination of at least twosubstances, in which one substance may be completely soluble, partiallysoluble or essentially insoluble in the other substance.

The term “solvent,” as used herein, means a substance, preferably aliquid or a miscible, partially miscible or immiscible mixture of two ormore liquids, which is capable of completely dissolving, partiallydissolving, dispersing or partially dispersing another substance,preferably a solid or a mixture of solids.

The term “anti-solvent,” as used herein, means a solvent in which acompound is essentially insoluble.

It is meant to be understood that, because many solvents andanti-solvents contain impurities, the level of impurities in solventsand anti-solvents for the practice of this invention, if present, are ata low enough concentration that they do not interfere with the intendeduse of the solvent in which they are present.

It is meant to be understood that peak heights in a powder x-raydiffraction pattern may vary and will be dependent on variables such asthe temperature, crystal size, crystal habit, sample preparation orsample height in the analysis well of the Scintag^(x)2 DiffractionPattern System.

It is also meant to be understood that peak positions may vary whenmeasured with different radiation sources. For example, Cu—Kα_(i),Mo—Kα, Co—Kα and Fe—Kα radiation, having wavelengths of 1.54060 Å,0.7107 Å, 1.7902 Å and 1.9373 Å, respectively, may provide peakpositions which differ from those measured with Cu—Kα radiation.

While digital outputs from powder x-ray diffractometers may be set toexpress peak positions to the one-hundredth and one-thousandth of adegree past the decimal, diffractometers are incapable of accurateexperimental determination beyond one-tenth of a degree. Accordingly,peak positions reported herein are rounded to one-tenth of a degree pastthe decimal.

Compositions made with or comprising a crystalline compound of thisinvention may be administered, for example, bucally, ophthalmically,orally, osmotically, parenterally (intramuscularly, intrasternally,intravenously, subcutaneously), rectally, topically, transdermally orvaginally. Ophthalmically administered dosage forms may be administeredas, for example, elixirs, emulsions, microemulsions, ointments,solutions, suspensions or syrups. Orally administered solid dosage formsmay be administered as, for example, capsules, dragees, emulsions,granules, pills, powders, solutions, suspensions, tablets,microemulsions, elixirs, syrups or powders for reconstitution.Osmotically and topically administered dosage forms may be administeredas, for example, creams, gels, inhalants, lotions, ointments, pastes orpowders. Parenterally administered dosage forms may be administered, as,for example, aqueous or oleaginous suspensions. Rectally and vaginallydosage forms may be administered, for example, as creams, gels, lotions,ointments or pastes.

The therapeutically acceptable amount of a crystalline compound of thisinvention depends on recipient of treatment, disorder being treated andseverity thereof, composition containing it, time of administration,route of administration, duration of treatment, its potency, its rate ofclearance and whether or not another drug is co-administered. The amountof a crystalline compound of this invention used to make a compositionto be administered daily to a patient in a single dose or in divideddoses is from about 0.03 to about 200 mg/kg body weight. Single dosecompositions contain these amounts or a combination of submultiplesthereof

A crystalline compound of this invention may be administered with orwithout an excipient. Excipients include, for example, encapsulatingmaterials or additives such as absorption accelerators, antioxidants,binders, buffers, coating agents, coloring agents, diluents,disintegrating agents, emulsifiers, extenders, fillers, flavoringagents, humectants, lubricants, perfumes, preservatives, propellants,releasing agents, sterilizing agents, sweeteners, solubilizers, wettingagents and mixtures thereof.

Excipients for preparation of compositions made with or comprising acrystalline compound of this invention to be administered orally insolid dosage form include, for example, agar, alginic acid, aluminumhydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol,carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, cornstarch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol,ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters,gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethylcelluose, isopropanol, isotonic saline, lactose, magnesium hydroxide,magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanutoil, potassium phosphate salts, potato starch, povidone, propyleneglycol, Ringer's solution, safflower oil, sesame oil, sodiumcarboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate,sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose,surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol,triglycerides, water, and mixtures thereof. Excipients for preparationof compositions made with a crystalline compound of this invention to beadministered ophthalmically or orally in liquid dosage forms include,for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil,ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil,glycerol, isopropanol, olive oil, polyethylene glycols, propyleneglycol, sesame oil, water and mixtures thereof.

Excipients for preparation of compositions made with a crystallinecompound of this invention to be administered osmotically include, forexample, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions made with a crystallinecompound of this invention to be administered parenterally include, forexample, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose,germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil,Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. orisotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions made with or comprising acrystalline compound of this invention to be administered rectally orvaginally include, for example, cocoa butter, polyethylene glycol waxand mixtures thereof

Solubilities of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylicacid in different buffered solutions at 25° C. are shown in TABLE 1.

TABLE 1 Medium Final pH Solubility (mg/mL) saline 5.8-5.9 0.013 0.1 HC10.8 0.00326 citrate buffer 4.0 4.2 0.00344 citrate buffer 5.0 5.10.00333 phosphate buffer 6.8 6.8 0.0668 phosphate buffer 7.4 7.4 0.283Phosphate Buffer 8.0 7.8 0.651 glycine buffer 9.0 8.2 2.49 0.1M NaOH 8.43.40 ethanol — 0.867

Solubilities of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylicacid in different base solutions at 25° C. are shown in TABLE 2.

TABLE 2 Base solution Solubility (mg/mL) K_(sp)(M²) S_(water) (mg/mL) 1MNaOH 8.33 1.66 × 10⁻² 56.8 0.5M KOH 24.4 1.69 × 10⁻² 57.4 1.0M TRIS 5.761.619 × 10⁻⁴  4.8 1M L-arginine 11.2 4.81 × 10⁻⁴ 9.67 1M meglumin 32.12.81 × 10⁻³ 23.6 1M ethanolamine 24.9 2.04 × 10⁻³ 19.9

The solubility of D-glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatetrihydrate (salt) in different base solutions at 25° C. is shown inTABLE 3.

TABLE 3 Final Solubility K_(sp) Medium pH (mg/mL) (M²) water 8.78 33.95.00 × 10⁻³ 0.01M meglumine 9.00 32.4 4.71 × 10⁻³ 0.1M meglumine 9.8332.2 4.16 × 10⁻³ 1M meglumine 10.85 30.8 3.34 × 10⁻³

The data in TABLES 1, 2 and 3 show the solubility effect of thecounterion of1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylicacid.

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention.

EXAMPLE 1

A mixture of1-(6-amino-3,5-difluoro2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(50 Kg) and 1-deoxy-1-(methylamino)-D-glucitol (26.1 Kg) was dilutedwith water (75.5 Kg) and isopropanol (60.2 Kg), stirred at 45° C.,cooled to 30±5° C., treated with isopropanol (175.7 Kg) whilemaintaining the internal temperature at about 30° C. and filtered. Thefiltrant was washed with isopropanol and dried under reduced pressure at30° C. for 12 hours then at 50° C. mp; 170-172° C. ¹H (D₂O/500 MHz) 8.22(d, J=0.76 Hz, 1H), 7.71 (d, J=14.19 Hz, 1H), 7.52 (dd, J=9.31, 0.77 Hz,1H), 4.58 (m, 2H), 4.53 (m, 1H), 4.15 (m, 3H), 3.83 (m, 2H), 3.774 (m,1H), 3.662 (m, 2H), 3.2 (m, 2H), 2.79 (s, 3H).

EXAMPLE 2

A mixture of1-(6-amino-3,5-difiuoro2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylate(29.6 Kg) and 1-deoxy-1-(methylamino)-D-glucitol (18.4 Kg) was dilutedwith water (133 Kg), stirred at 60° C. until all solids dissolved,cooled to 38° C. and held there until solid formed, cooled to 0° C. andfiltered. The filtrant was washed with isopropanol and dried at 50° C.

The foregoing is merely illustrative of the invention and is notintended to limit the same to disclosed embodiments. Variations andchanges obvious to one skilled in the art are intended to be within thescope and nature of the invention as defined in the appended claims.

what is claimed is:
 1. A therapeutic composition comprising D-Glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatesalt, at least one filler, at least one binder, at least onedisintegrating agent, at least one buffering agent and at least onelubricant.
 2. The composition of claim 1, wherein the salt is present ina therapeutically acceptable amount.
 3. The composition of claim 1,wherein the salt is crystalline.
 4. The composition of claim 3, whereinthe salt has substantial crystalline purity.
 5. The composition of claim4, wherein the salt has at least about 95% crystalline purity.
 6. Thecomposition of claim 3, wherein the salt is characterized, when measuredat about 25° C. with Cu—Kα radiation, by the powder diffraction patternshown in FIG.
 1. 7. The composition of claim 3, wherein the salt ischaracterized by respective lattice parameters, a, b, and c of about16.4460 Å, 21.4010 Å, and 5.3050 Å and β of about 109° in the monocliniccrystal system P 21/C or P 21/M space group, when measured with Mo—Kαradiation at about 25° C.
 8. The composition of claim 1, wherein thesalt has substantial chemical purity.
 9. The composition of claim 8,wherein the salt is about 97% chemically pure.
 10. The composition ofclaim 8, wherein the salt is about 98% chemically pure.
 11. Thecomposition of claim 8, wherein the salt is about 100% chemically pure.12. The composition of claim 1, wherein the composition is an orallyadministered dosage form.
 13. The composition of claim 1, wherein the atleast one filler comprises cellulose.
 14. The composition of claim 1,wherein the at least one binder comprises povidone.
 15. The compositionof claim 1, wherein the at least one disintegrating agent comprisescross-povidone.
 16. The composition of claim 1, wherein the at least onebuffering agent comprises a sodium phosphate salt.
 17. The compositionof claim 1, wherein the at least one buffering agent comprises acitrate.
 18. The composition of claim 1, wherein the at least onelubricant comprises magnesium stearate.
 19. The composition of claim 1,wherein the at least one filler comprises cellulose, the at least onebinder comprises povidone, the at least one disintegrating agentcomprises cross-povidone, the at least one buffering agent comprises asodium phosphate salt, and the at least one lubricant comprisesmagnesium stearate.
 20. The composition of claim 19, further comprisinga citrate.
 21. A therapeutic composition comprising D-Glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatesalt, cellulose, povidone, cross-povidone, a sodium phosphate salt andmagnesium stearate.
 22. The therapeutic composition of claim 21, furthercomprising a citrate.
 23. A method of treating a bacterial infection ina fish or a mammal comprising administering thereto a compositioncomprising a therapeutically acceptable amount of D-Glucitol,1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatesalt, at least one filler, at least one binder, at least onedisintegrating agent, at least one buffering agent and at least onelubricant.
 24. The method of claim 21, wherein the composition isadministered to a mammal.
 25. The method of claim 21, wherein thetherapeutically acceptable amount is from about 0.03 to about 200 mg/kgbody weight.
 26. The method of claim 21, wherein the at least one fillercomprises cellulose.
 27. The method of claim 21, wherein the at leastone binder comprises povidone.
 28. The method of claim 21, wherein theat least one disintegrating agent comprises cross-povidone.
 29. Themethod of claim 21, wherein the at least one buffering agent comprises asodium phosphate salt.
 30. The method of claim 21, wherein the at leastone buffering agent comprises a citrate.
 31. The method of claim 21,wherein the at least one lubricant comprises magnesium stearate.
 32. Themethod of claim 21, wherein the at least one filler comprises cellulose,the at least one binder comprises povidone, the at least onedisintegrating agent comprises cross-povidone, the at least onebuffering agent comprises a sodium phosphate salt, and the at least onelubricant comprises magnesium stearate.
 33. The method of claim 32,further comprising a citrate.
 34. A method of treating a bacterialinfection in a fish or a mammal comprising administering thereto acomposition comprising a therapeutically acceptable amount ofD-Glucitol, 1-deoxy-1-(methylamino)-,1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxyazetidin-1-yl)-4-oxo-3-quinolinecarboxylatesalt, at least one filler, cellulose, povidone, cross-povidone, a sodiumphosphate salt and magnesium stearate.
 35. The method of claim 34,further comprising a citrate.